Bone tissue contains high concentrations of calcium, usually in the form of crystalline hydroxyapatite, i.e. Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2. Hydroxyapatite--and the calcium of the bone--exist in equilibrium with body fluids, particularly blood. Although the calcium and hydroxyapatite are soluble in blood, the equilibrium is maintained in healthy individuals, along with a stable and intact bone matrix. Since bone is living tissue, it is constantly being remodeled. Certain bone cells, known as osteoblasts, promote bone formation. Other bone cells, known as osteoclasts, tend to cause bone dissolution. The biological process of calcification is critical in providing the mechanical strength for the skeleton and teeth. Pathological states associated with accelerated bone resorption and loss of bone mineral lead to disease characterized by skeletal dysfunction and life-threatening metabolic disorders.
Loss of bone mass from increased bone resorption results in accelerated loss of calcium into the blood. Accelerated bone loss is a major cause of illness in the United States which affects millions of individuals. When significant depletion of bone calcium occurs and the structural integrity of the skeleton is compromised, several diseases result. An example of a disease state associated with severe loss of bone mass is osteoporosis, a major cause of hip and vertebral fractures in older women. Hypercalcemia, or increased blood calcium concentration, occurs frequently in patients who suffer from hyperparathyroidism or cancer. This bone resorptive disorder can lead to kidney failure, coma, and death. Bone metastasis, or the spread of cancer cells into bone, occurs in many patients with cancer and causes progressive bone erosion, fractures, and pain. All of these conditions would be ameliorated by drugs which decrease bone resorption and potentially increase bone tissue calcium content.
Clearly, then, there has been a long-standing need for a treatment which would prevent resorption of calcium from bone. Further, by affecting the balance between resorption and new bone formation, one would also expect that such drugs would increase the rate of calcium accretion in bone.
It has been found that compounds containing the metal gallium, and gallium nitrate in particular, are effective in reducing excessive loss of bone calcium in humans. This method has been disclosed and patented by applicants' U.S. Pat. No. 4,529,593 (7/16/85) the disclosure of which is incorporated by reference. There was no teaching until the present, however that other metal-containing compounds could also decrease bone resorption.
Other metal-containing compounds, so defined by virtue of their relative position in the Periodic Table of the Elements, and their elemental electropositivity, malleability, and conductivity, also interact with bone cells or with the crystalline bone matrix and thereby favorably alter the balance between bone formation and resorption. This supposition has been proven by experiments disclosed herein.
It has been found that metal-containing compounds act on bone tissue to decrease the rate of calcium loss when resorption is stimulated. These metallic compounds retard the destruction of preexisting bone tissue (so called "osteolysis") as a result of various disorders (e.g., metastasis of cancer tumors; hypercalcemia caused by cancer; parathyroid hormone or lymphokine-related compounds; osteoporosis, periodontal disease; or increased bone cell resorbing activity). The metallic compounds used have a low order of toxicity and are pharmaceutically acceptable. They are administered in sufficient dosages to be effective. The effective amount and route of administration (e.g., intravenous, oral, topical, etc.) of the particular compound will vary based upon the nature of the disease being treated, its severity, the age of the patient, and other factors which will be apparent to one skilled in the art.
The following particulars of the invention describe preferred aspects thereof. These particulars, however, should not be taken as limitations to the invention as described, but only of examples of particular, preferred embodiments.